Human length telomeres restrict the regenerative potential of hematopoietic stem cells in mice

Telomere biology disorders (TBDs), including dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson syndrome (HHS), demonstrate that critically short telomeres cause bone marrow failure. Mutations in RTEL1, encoding a telomere-associated helicase, are among the genetic causes of DC and HHS. However, whether telomere length variation within the physiological human range affects hematopoietic function remains poorly understood. We investigated this question using the "Telomouse" model, which harbors a single amino acid substitution in Rtel1 (Rtel1^M492K/M492K) that results in human-length telomeres rather than the considerably longer telomeres characteristic of wild-type Mus musculus. Although Telomice maintain normal steady-state hematopoiesis, proliferative stress induced by serial 5-fluorouracil treatment or bone marrow transplantation into lethally irradiated recipients revealed significant depletion of bone marrow progenitor cells compared to wild-type controls. Nanopore sequencing and fluorescence in situ hybridization demonstrated an elevated frequency of critically short telomeres in stressed Telomouse hematopoietic cells, accompanied by increased DNA damage (γH2AX foci) and apoptotic signaling (cleaved caspase-3). These findings establish that telomere length within the normal human range represents a critical determinant of hematopoietic reserve capacity under proliferative stress, with implications for understanding individual variation in bone marrow resilience and TBD pathophysiology.